Synthesis of some new derivatives of thiazolopyrimidines and hydrolysis of its arylidene derivative

Article abstract of DOI:10.1007/s12039-015-0797-y

A new ammonium acetate-assisted, convenient and efficient procedure for the synthesis of arylidene derivatives of thiazolopyrimidine is described. The main advantages of this protocol is that it is economical, short reaction time, commonly available chemicals, and ease of isolation of products. In addition, a new series of thiazole-fused pyrimidines were synthesized and hydrolysis of one of its arylidene derivative studied. All the compounds were characterized by analytical and spectroscopic methods. Further, the structure of hydrolyzed product and two other compounds were confirmed by X-ray crystal structure analysis. The crystal structures are stabilized by intermolecular C-H.O, C-H.N, C-H.π and π.π weak interactions. The anti-microbial screening was done on the compounds in order to test their anti-bacterial and anti-fungal activities. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-015-0797-y

J. Chem. Sci. Vol. 127, No. 3, March 2015, pp. 467–479. ꢀc Indian Academy of Sciences.
DOI 10.1007/s12039-015-0797-y
Synthesis of some new derivatives of thiazolopyrimidines and hydrolysis
of its arylidene derivative
a
b
a,∗
H NAGARAJAIAH , IMTIYAZ AHMED M KHAZI and NOOR SHAHINA BEGUM
a
Department of Chemistry, Bangalore University, Central College Campus, Bangalore 560001, India
Department of Chemistry, Karnatak University, Dharwad 580003, India
b
e-mail: noorsb05@gmail.com; noorsb@rediffmail.com
MS received 16 May 2014; revised 12 September 2014; accepted 7 October 2014
Abstract. A new ammonium acetate-assisted, convenient and efficient procedure for the synthesis of arylidene
derivatives of thiazolopyrimidine is described. The main advantages of this protocol is that it is economical,
short reaction time, commonly available chemicals, and ease of isolation of products. In addition, a new series
of thiazole-fused pyrimidines were synthesized and hydrolysis of one of its arylidene derivative studied. All the
compounds were characterized by analytical and spectroscopic methods. Further, the structure of hydrolyzed
product and two other compounds were confirmed by X-ray crystal structure analysis. The crystal structures are
stabilized by intermolecular C-H. . .O, C-H. . .N, C-H. . . π and π . . . π weak interactions. The anti-microbial
screening was done on the compounds in order to test their anti-bacterial and anti-fungal activities.
Keywords. Thiazolo[3,2−a]pyrimidines; hydrolysis of arylidene derivative; crystal structure; anti-microbial
activity.
1
. Introduction
use of ammonium acetate under warm condition with
ethanol as a solvent medium. It is a convenient and fast
protocol, although the synthetic route followed is a con-
ventional one. However, the duration of the reaction is
very short, as it goes to completion in 10 min. This is
yet another advantage of the present protocol.
In continuation of our work with thiazolopyrimi-
dines, we report herein the synthesis of some new
derivatives and a tricyclic thiazolopyrimidine. It has
been observed that the hydrolysis of arylidene deriva-
tive of thiazolopyrimidine occurs via rupture of imine
bond under acidic condition. In this paper, the mecha-
nism for hydrolysis has been proposed. Some of these
derivatives exhibit promising anti-microbial activities.
We have presented here the crystal structure analysis of
the two derivatives. The structure analysis was under-
taken to determine the configuration and conformation
of the molecule and the orientation of the substituents
around the thiazolopyrimidine framework.
Heterocycles containing sulphur and nitrogen are of
great interest because they constitute an important class
of natural and synthetic organic molecules, many of
which exhibit useful biological activity. One such hete-
rocyclic class is thiazolopyrimidines. These have gene-
rated interest in recent years due to their biological
and pharmaceutical activities. These ring systems have
shown anti-microbial,
matory,
tubercular activity. In addition, they have been reported
to possess anti-tumour activity9 and have also shown
to possess anti-parkinsonian and anti-proliferative
1
–4
anti-malarial,5 anti-inflam-
6
,7
anti-oxidant,6 anti-nociceptive7 and anti-
8
,10
11
properties.
In view of all these observations, we have under-
taken the synthesis of some new derivatives of thiazolo
[
3,2-a]pyrimidines. The traditional methods7,12–14 to
synthesize arylidene derivative involve the use of 1:1
mixture of acetic acid and acetic anhydride in presence
of sodium acetate. But this method is not satisfactory
with regard to the isolation of the products and also 2. Experimental
due to the drastic reaction conditions that are employed.
To overcome this limitation, we have developed a new
2.1 Materials and methods
protocol for the synthesis of arylidene derivative of All the chemicals were purchased from S D Fine and
thiazolopyrimidines using readily available, inexpen- Spectrochem used as received without further purifi-
sive and environment-friendly catalysts. We have made cation. Melting point apparatus was used to determine
the melting point in open capillaries and are uncorrected.
IR spectra were recorded on Nicolet Impact 400D FT-IR
∗
For correspondence
467

468
H Nagarajaiah et al.
◦
−1
spectrophotometer using KBr pellets. Bruker 400 MHz 82%, M.p.: 241–242 C. IR (KBr) v cm : 2981 (CH),
1
FT-NMR spectrometer was used to record H and 1698 (C=O), 1599 (C=C), 1491 (C=N), 1215 (C-O).
13
1
C NMR in CDCl and DMSO-d with TMS as inter-
H NMR (400 MH , CDCl ) δ ppm: 1.18 (t, J=7.2
2 3 3
3
6
Z
3
nal standard. The reactions and purity of the products Hz, 3H, CH CH ), 2.37 (s, 3H, CH ), 4.09 (q, J=7.2
were monitored by TLC silica gel plates. Mass spec- Hz, 2H, CH CH ), 6.19 (s, 1H, C5-H), 7.26–7.74 (m,
2
3
tra were recorded on LC-MSD-Trap-SL spectrometer 9H, Ar-H), 9.62 (s, 1H, OH), 13.10 (s, 1H, COOH).
1
3
and elemental analyses were carried out using CHNS
Elimentar (Vario-micro cube).
C NMR (400 MH , CDCl ) δ ppm: 14.76, 23.30,
Z 3
54.86, 60.09, 100.14, 109.91, 122.96, 127.15–141.04,
1
1
45.28, 153.04, 156.04, 164.99, 165.69, 166.23,
67.47. %CHNS found (calc): C 62.06 (62.12), H 4.34
2.2 Procedure for the synthesis of compounds 2(a–d)
(4.52), N 6.03 (6.31), S 6.90 (6.61).
A mixture of ethyl 3,5-dihydro-7-methyl-3-oxo-5-
phenyl-2H-thiazolo[3,2−a]pyrimidine-6-carboxylate
2
5
.2d (2Z)-methyl 2-(3-fluorobenzylidene)-3,5-dihydro-
-(4-hydroxyphenyl)-7-methyl-3-oxo-2H-thiazolo[3,2-
(
1a/1d/1e) (10 mmol), aromatic aldehydes (10 mmol)
and catalytic amount of ammonium acetate in ethanol
a]pyrimidine-6-carboxylate (2d): Yellow solid, yield
(30 mL) was warmed for 5–10 min with constant stir-
◦
−1
84%, M.p.: 286–287 C. IR (KBr) v cm : 2976 (CH),
ring. The reaction mixture was allowed to stand at
room temperature for 30 min. The solid thus separated
was filtered and washed with water and recrystsallized
from ethanol to afford yellow compound with good
yield 82–87%.
1
701 (C=O), 1598 (C=C), 1497 (C=N), 1192 (C-O).
1
H NMR (400 MH , CDCl ) δ ppm: 2.36 (S, 3H, CH ),
Z
3
3
3
.67 (s, 3H, OCH ), 6.02 (s, 1H, C5-H), 6.75–7.83
3
13
(m, 9H, Ar-H), 9.60 (s, 1H, OH). C NMR (400 MH ,
Z
CDCl ) δ ppm: 23.26, 55.44, 60.12, 100.14, 116.29,
3
2
3
.2a (2Z)-Ethyl 2-benzylidene-3,5-dihydro-7-methyl- 122.96, 127.15, 128.4–137.63, 141.04, 145.78, 154.03,
-oxo-5-phenyl-2H-thiazolo[3,2-a] pyri -midine-6-car- 162.31, 164.72, 165.59, 167.42. %CHNS found (calc):
boxylate (2a): Yellow solid, yield 87%, M.p.: 178– C 62.25 (62.42), H 4.04 (4.06), N 6.60 (6.83), S 7.55
◦
−1
1
(
79 C. IR (KBr) v cm :2978(CH), 1711 (C=O), 1608 (7.59).
1
C=C), 1484 (C=N), 1169 (C-O). H NMR (300 MH ,
Z
CDCl ) δ ppm: 1.18 (t, J=7.2 Hz, 3H, CH CH ), 2.52
3
2
3
2.3 Procedure for the hydrolyzed compound 3
(
(
s, 3H, CH ), 4.11 (q, J=7.2 Hz, 2H, CH CH ), 6.22
3
2
3
s, 1H, C5-H), 7.26–7.45 (m, 10H, ArH). 7.73(s, 1H,
2
.3a Method 1: Compound 1a was refluxed with
13
arylidene-H). C NMR (300 MH , CDCl ) δ ppm:
Z
3
benzaldehyde in presence of ammonium acetate in
acetic acid for 5–6 h with constant stirring. The reac-
tion mixture was allowed to stand at room temperature
overnight. The solid thus separated was filtered, washed
with water and recrystallized from ethanol to afford
pale yellow crystals in good yield (82%).
1
1
1
4.98, 23.42, 55.13, 60.35, 102.08, 108.88, 114.16,
27.41, 128.15, 129.62, 130.96, 132.43, 134.09,
44.51, 154.62, 159.62, 163.14, 165.62, 167.73.
CHNS found (calc): C 68.30 (68.41), H 4.98 (5.13),
N 6.93 (6.82), S 7.93 (8.13).
%
2
5
.2b (2Z)-Methyl 2-(3-cyanobenzylidene)-3,5-dihydro-
-(4-hydroxyphenyl)-7-methyl-3-oxo-2H-thiazolo[3,2-
2
.3b Method 2: A mixture of compound 2a and cat-
alytic amount of conc. HCl in ethanol (100 mL) was
refluxed for 5–6 h with constant stirring. The reac-
tion mixture was allowed to stand room temperature
overnight. The solid thus separated was filtered, washed
with water and recrystsallized from ethanol to afford
good quality crystals (yield 80%).
a]pyrimidine-6-carboxylate (2b): Yellow solid, yield
◦
−1
84%, M.p.:234–235 C. IR (KBr) v cm : 2987 (CH),
1
698 (C=O), 1603 (C=C), 1486 (C=N), 1231 (C-O).
1
H NMR (400 MH , DMSO-d ) δ ppm: 2.38 (S, 3H,
Z
6
CH ), 3.60 (s, 3H, OCH ), 5.96 (s, 1H, C5-H), 6.95–
3
3
7
(
.95 (m, 9H, Ar-H), 9.58 (s, 1H, Ar-OH). 13C NMR
400 MH , DMSO-d ) δ ppm: 23.31, 54.86, 61.15,
Z
6
2.3c (Z)-5-Benzylidenethiazolidine-2,4-dione(3): Colour-
100.14, 122.96, 127.15, 128.4–137.63, 141.04, 145.78,
1
◦
less solid, yield 82%, M.p.: 264–265 C. IR (KBr) v
cm : 3145 (NH), 3037 (CH), 1739 (SCONH),
1
53.04, 164.99, 165.69, 167.47. Mass (m/z): 432.22
−1
+
[
3
M+H] . %CHNS found (calc): C 64.03 (64.32), H
1
691 (CONH), 1606 (C=C), 1336 (C-N). H NMR
.97 (3.76), N 9.74 (9.63), S 7.43 (7.59).
(300 MH , DMSO-d ) δ ppm: 7.42–7.58 (m, 5H, Ar-H),
Z
6
2.2c 4-((1Z)-(6-(ethoxycarbonyl)-5-(4-hydroxyphenyl)-7 7.75 (s, 1H, arylidene-H), 12.58 (s, 1H, NH), %CHNS
-methyl-3-oxo-3H-thiazolo[3,2-a] pyrimidin-2(5H)-yli- found (calc): C 58.52 (58.63), H 3.44 (3.23), N 6.82
dene)methyl)benzoic acid (2c): Yellow solid, yield (6.67), S 15.62 (15.67).

Thiazolo[3,2-a]pyrimidines
469
2
.4 General procedure for the synthesis compounds
2.5 General procedure for the synthesis of compounds
5 (a–d)
4a and 4b
A mixture of ethyl 3,5-dihydro-7-methyl-3-oxo-5- A mixture of compound 1(a–d) (10 mmol) and DMF–
substituted phenyl-2H-thiazolo[3,2−a]pyrimidine-6- DMA (5 mL) was heated under reflux for 2 h. The reac-
carboxylate (5 mmol), morpholine (6 mmol), formalin tion mixture was triturated with ethanol to give a solid
(1 mL) and acetic acid (1 mL) in methanol (20 mL) was product that was collected by filtration and crystallized
refluxed for 8 h (monitored by TLC). Reaction mixture from ethanol to give compounds 5(a–d) as deep orange
was diluted with water and extracted with chloroform crystals with yield of 85–89%.
(
3 × 30 mL). The combined chloroform extract was
washed with water (3 × 30 mL) and dried over anhy-
drous sodium sulfate. The solvent was removed under
vacuum and the residue was recrystallized from ben-
zene and hexane mixture to yield colorless to yellow
granules with good yield 82–87%.
2.5a 2-Dimethylaminomethylene-7-methyl-3-oxo-5-
phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimi -dine-6-
carboxylic acid ethyl ester (5a): Orange yellow solid,
◦
−1
yield 87%, M.p.: 204–205 C. IR (KBr) v cm :2983
(
(
CH), 1710 (C=O), 1618 (C=C), 1490 (C=N), 1179
1
C-O). H NMR (400 MH , CDCl ) δ ppm: 1.17 (t,
Z
3
J=7.2 Hz, 3H, CH CH ), 2.47 (s, 3H, CH ), 3.10 (s,
2
.4a (2Z)-ethyl 3,5-dihydro-7-methyl-2-(morpholino-
methyl)-3-oxo-5-phenyl-2H-thiazolo [3,2-a]pyrimidine-
-carboxylate (4a): Pale yellow solid, yield 87%,
2
3
3
6
H, 2XCH ), 4.08 (q, J=7.2 Hz, 2H, CH CH ), 6.16
3
2
3
(
s, 1H, C5-H), 7.19–7.39 (m, 5H, Ar-H), 7.49 (s, 1H,
6
13
◦
−1
=CH-NMe ). C NMR (400 MHz, CDCl ) δ ppm:
M.p.: 84–85 C. IR (KBr) v cm : 2982 (CH), 1711
2
3
1
4.14, 23.02, 54.87, 59.99, 86.06, 106.03, 127.82-
128.34, 141.71, 145.73, 154.32, 166.05, 166.15.
CHNS found (calc): C 61.44 (61.41), H 5.70 (5.76),
(
C=O), 1613 (C=C), 1499 (C=N), 1180 (C-O).
1
H NMR (400 MH , CDCl ) δ ppm: 1.16 (t, J=7.2
Z
3
%
Hz, 3H, CH CH ), 2.38 (s, 3H, CH ), 2.47 (t, J=4.5
2
3
3
N 11.31 (11.33), S 8.63 (8.59).
Hz, 4H, C , C -H, morpholine), 3.00 (d, J=4.1 Hz,
3
5
2
(
H, CH -N), 3.36 (t, J=4.3 Hz, 1H, S-CH), 3.63
2
t, J=4.3 Hz, 4H, C , C -H, morpholine), 4.07 (q,
2
6
2.5b 2-Dimethylaminomethylene-5-(3-methoxy-phenyl)-
7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimi-
dine-6-carboxylic acid ethyl ester (5b): Orange yel-
J=7.2 Hz, 2H, CH CH ), 5.99 (s, 1H, C5-H), 7.26–
2 3
7
.36 (m, 5H, Ar-H). 13C NMR (400 MH , CDCl ) δ
Z 3
ppm: 14.06, 22.27, 50.48, 54.11, 55.37, 57.23, 59.19,
◦
low solid, yield 89%, M.p.: 181–182 C. IR (KBr) v
6
1
0.51, 101.16, 117.23, 127.9–136.32, 140.07, 144.98,
55.13, 161.92, 164.29, 166.01, 167.13. %CHNS found
−1
cm : 3033, 2987 (CH), 1714 (C=O), 1620 (C=C),
1
1
499 (C=N), 1173 (C-O). H NMR (400 MH ,
Z
(calc): C 60.70 (60.49), H 6.06 (5.76), N 10.11 (10.33),
CDCl ) δ ppm: 1.19 (t, J=7.2 Hz, 3H, CH CH ), 2.47
3
2
3
S 7.72 (7.59).
(
s, 3H, CH ), 3.11 (s, 6H, 2XCH ), 3.75 (s, 3H, OCH ),
3 3 3
4
6
.09 (q, J=7.2 Hz, 2H, CH CH ), 6.15 (s, 1H, C5-H),
2
3
.75–7.26 (m, 4H, Ar-H), 7.53 (s, 1H, =CH-NMe ).
2
2
.4b (2Z)-ethyl 3,5-dihydro-5-(3-methoxyphenyl)-7-
1
3
C NMR (400 MHz, CDCl ) δ ppm: 14.19, 22.93,
3
methyl-2-(morpholinomethyl)-3-oxo-2H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4b): Pale yellow solid,
yield 82%, M.p.: 88–89 C. IR (KBr) v cm :2996
54.59, 60.06, 61.32, 86.43, 106.27, 127.85–128.54,
140.36, 141.55, 145.82, 154.41, 165.89, 166.32. Mass
◦
−1
+
(
(
m/z): 402.3 [M+H] . %CHNS found (calc): C 59.83
(
(
CH), 1707 (C=O), 1601 (C=C), 1512 (C=N), 1172
60.12), H 5.77 (5.76), N 10.47 (10.33), S 7.99 (7.95).
1
C-O). H NMR (400 MH , CDCl ) δ ppm: 1.17 (t,
Z
3
J=7.2 Hz, 3H, -CH CH ), 2.36 (s, 3H, CH ), 2.47
2
3
3
(
t, J=4.5 Hz, 4H, C , C -H, morpholine), 3.08 (d, 2.5c 2-Dimethylaminomethylene-5-(4-methoxy-phenyl)
3
5
J=4.1 Hz, 2H, CH ), 3.33 (t, J=4.3 Hz, 1H, S-CH), -7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimi-
2
3
3
(
.65 (t, J=4.3 Hz, 4H, C , C -H, morpholine), 3.79 (s, dine-6-carboxylic acid ethyl ester (5c): Orange yel-
◦
3 2 3
2
6
H, OCH ), 4.10 (q, J=7.2 Hz, 2H, CH CH ), 6.05 low solid, yield 85%, M.p.: 165–167 C. IR (KBr) v
1
3
−1
s, 1H, C5-H), 7.13–7.41 (m, 4H, Ar-H). C NMR cm :3035, 2996 (CH), 1711 (C=O), 1600 (C=C),
1
(
400 MH , CDCl ) δ ppm: 13.98, 22.19, 50.43, 1498 (C=N), 1215 (C-O). H NMR (400 MH ,
Z
3
Z
5
1
1
4.17, 55.90, 57.71, 59.42, 60.18, 61.41, 100.43, CDCl ) δ ppm: 1.18 (t, J=7.2 Hz, 3H,-CH CH ),
3
2
3
19.19, 126.36–138.50, 140.57, 144.02, 155.19, 2.51 (s, 3H, CH ), 3.13 (s, 6H, 2XCH ), 3.75 (s, 3H,
3
3
61.92, 163.41, 165.97, 167.11. %CHNS found -OCH ), 4.09 (q, J=7.2 Hz, 2H, CH CH ), 6.14 (s, 1H,
3
2
3
(
calc): C 59.31 (59.23), H 6.11 (6.37), N 9.43 (9.22), C5-H), 6.78–7.33 (m, 4H, Ar-H), 7.55 (s, 1H, =CH-
13
S 7.20 (7.47).
NMe ). C NMR (400 MHz, CDCl ) δ ppm: 14.03,
2
3

470
H Nagarajaiah et al.
2
1
1
3.21, 54.89, 59.93, 61.10, 87.33, 106.05, 127.52, dene)methylamino)benzoic acid (6b): Yellow solid,
28.87, 139.59, 141.76, 145.32, 154.19, 166.27, yield 63%, M.p.:220–221 C. IR (KBr) v cm :3342
◦
−1
67.02. %CHNS found (calc): C 59.83 (60.12), H 5.77 (-OH), 2987 (CH), 1710 (ester C=O), 1691 (COOH),
1
(5.76), N 10.47 (10.33), S 7.99 (7.95).
1503 (C=C), 1052 (C-O). H NMR (400 MH , DMSO-
Z
d ) δ ppm: 1.11 (t, J=7.2 Hz, 3H, CH CH ), 2.23
6
2
3
(
s,3H, CH ), 3.79 (s,3H, OCH ), 3.99 (q, J=7.2 Hz,
3
3
2.5d 2-Dimethylaminomethylene-5-(4-hydroxy-phenyl)
2
9
H, CH ), 5.73 (s, 1H, C5-H), 6.76–8.05(m, 9H, Ar-H),
2
-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimi-
13
.88 (d, 1H, NH), 11.85 (s, 1H, -COOH). C NMR
dine-6-carboxylic acid ethyl ester (5d): Orange yel-
low solid, yield 87%, M.p.: 280–281 C. IR (KBr)
(
5
1
(
400 MH , DMSO-d ) δ ppm:14.23, 17.68, 53.70,
5.25, 59.15, 112.10, 112.35, 115.26–134.39, 144.54,
46.30, 159.60, 167.20. %CHNS found (calc): C 60.84
Z 6
◦
−1
v cm : 3321 (OH), 2979 (CH), 1712 (C=O), 1623
1
(
C=C), 1492 (C=N), 1183 (C-O). H NMR (400 MH ,
Z
60.99), H 4.70 (4.63), N 8.51 (8.67), S 6.50 (6.38).
CDCl ) δ ppm: 1.21 (t, J=7.2 Hz, 3H, CH CH ), 2.64
3
2
3
(
2
s, 3H, CH ), 3.22 (s, 6H, 2XCH ), 4.12 (q, J=7.2 Hz,
3
3
2.7 General procedure for the synthesis of compounds
H, CH CH ), 6.13 (s, 1H, C5-H), 6.74–7.09 (m, 4H,
2 3
7
(a–f)
Ar-H), 7.59 (s, 1H, =CH-NMe ), 9.60 (s, 1H, -OH).
2
13
C NMR (400 MHz, CDCl ) δ ppm: 13.90, 23.01,
3
To a solution of 5a/5b (5 mmol) in ethanol (30 mL) sec-
ondary amines like morpholine, piperidine and pyrro-
lidine (5 mmol) was added and then refluxed for sev-
eral hours. Completion of the reaction was monitored
by TLC. The solid separated was filtered and dried to
get the desired product.
5
1
4.47, 60.06, 86.88, 107.03, 124.72, 127.40, 143.76,
45.19, 154.62, 165.95, 166.31. %CHNS found (calc):
C 58.90 (58.76), H 5.46 (5.59), N 10.85 (10.63), S 8.28
8.31).
(
2.6 General procedure for the synthesis of compounds
6a and 6b
2.7a 7-Methyl-2-morpholin-4-ylmethylene-3-oxo-5-phe-
nyl-2,3-dihydro-5H-thiazolo[3,2-a] pyrimidine-6-car-
A mixture of 2-dimethylaminomethylene-7-methyl-
-oxo-5-substituted phenyl-2,3-dihydro-5H-thiazolo
boxylic acid ethyl ester (7a): Pale orange yel-
3
◦
low solid, yield 80%, M.p.:221–222 C. IR (KBr) v
[
(
3,2−a]pyrimidine-6-carboxylic acid ethyl ester
−1
cm :2982 (CH), 1705 (C=O), 1612 (C=C), 1502
5 mmol), 2-amino benzoic acid (5 mmol) and acetic
1
(
C=N), 1192 (C-O). H NMR (400 MH , CDCl ) δ
Z
3
acid (1 mL) in methanol (30 mL) was refluxed for
h (monitored by TLC). The excess methanol was
ppm: 1.17 (t, J=7.2 Hz, 3H, CH CH ), 2.50 (s, 3H,
2
3
8
CH ), 3.45 (t, J=4.8 Hz, 4H, CH CH ), 3.73 (t, J=4.8
3
2
2
removed under reduced pressure. The compound was
diluted with water. The solid thus separated was filtered
and dried to give yellow compound with 60–63% yield.
Hz, 4H, CH CH ), 4.09 (q, J=7.2 Hz, 2H, CH CH ),
2
2
2
3
6
1
.17 (s, 1H, C5-H), 7.23–7.40 (m, 5H, Ar-H), 7.49 (s,
1
3
H,=CH-N(CH ) ). C NMR (400 MH , CDCl ) δ
2
2
Z
3
ppm: 14.16, 23.02, 55.57, 57.03, 59.89, 60.15, 100.18,
2.6a 2-((1Z)-(6-(ethoxycarbonyl)-7-methyl-3-oxo-5-
1
1
17.54, 125.79–137.27, 140.04, 144.56, 155.29,
61.09, 164.61, 166.26, 167.01. %CHNS found (calc):
phenyl-3H-thiazolo[3,2-a]pyrimidin-2 (5H)-ylidene)methy
lamino)benzoic acid (6a): Yellow solid, yield 60%,
C 61.00 (61.10), H 5.61 (5.66), N 10.16 (10.31), S 7.75
7.93).
◦
−1
M.p.:244–245 C. IR (KBr) v cm : 3340 (OH),
(
2
994(CH), 1712 (ester C=O), 1690 (COOH), 1510
1
(
C=C), 1042(C-O). H NMR (400 MH , DMSO-d ) δ
Z
6
2.7b 5-(3-Methoxy-phenyl)-7-methyl-2-morpholin-4-
ppm: 1.10 (t, J=7.2 Hz, 3H, CH CH ), 2.21 (s,3H,
2
3
ylmethylene-3-oxo-2,3-dihydro-5H-thia -zolo[3,2-a]py-
CH ), 3.99 (q, J=7.2 Hz, 2H, CH ), 5.72 (s, 1H, C5-H),
3
2
rimidine-6-carboxylic acid ethyl ester (7b): Pale
6
.63–8.03(m, 8H, Ar-H), 9.87 (d,1H, NH), 11.83(s, 1H,
◦
13
orange yellow solid, yield 78%, M.p.:214–215 C. IR
COOH). C NMR (400 MH , DMSO-d ) δ ppm:14.02,
Z
6
−
1
(
(
KBr) v cm : 3037, 2956 (CH), 1703 (C=O), 1610
1
1
7.70, 53.72, 59.14, 112.10, 112.35, 114.44–132.25,
45.41, 146.32, 159.61, 167.29. %CHNS found (calc):
1
C=C), 1501 (C=N), 1198 (C-O). H NMR (400 MH ,
Z
CDCl ) δ ppm: 1.18 (t, J=7.2 Hz, 3H, CH CH ), 2.51
3
2
3
C 62.19 (62.34), H 4.57 (4.53), N 9.07 (8.88), S 6.92
6.97).
(
(
s, 3H, CH ), 3.43 (t, J=4.8 Hz, 4H, CH CH ), 3.73
3
2
2
(
t, J=4.8 Hz, 4H, CH CH ), 4.05 (q, J=7.2 Hz, 2H,
2 2
CH CH ), 6.12 (s, 1H, C5-H), 7.27–7.64 (m, 4H, Ar-
2
3
13
2
.6b 2-(-(6-(ethoxycarbonyl)-5-(3-methoxyphenyl)-7- H), 7.51 (s, 1H, =CH-N(CH ) ). C NMR (400 MH ,
2
2
Z
methyl-3-oxo-3H-thiazolo[3,2-a]pyrimi -din-2(5H)-yli- CDCl ) δ ppm: 14.01, 23.12, 55.47, 57.17, 58.03,
3

Thiazolo[3,2-a]pyrimidines
471
5
1
9.67, 60.18, 100.04, 119.21, 125.63–137.37, 140.16, 155.37, 160.51, 164.62, 166.17, 167.02. %CHNS
44.37, 154.48, 160.59, 164.16, 166.66, 167.13. found (calc): C 63.45 (63.23), H 5.83 (5.67), N 10.57
%
CHNS found (calc): C 59.58 (59.62), H 9.47 (9.71), (10.61), S 8.07 (7.97).
N 9.47 (9.38), S 7.23 (7.15).
2
.7f Ethyl 3,5-dihydro-5-(3-methoxyphenyl)-7-methyl-
3-oxo-2-((pyrrolidin-1-yl)methylene)-2H-thiazolo[3,2-a]
lene-2,3-dihydro-5H-thiazolo[3,2-a] pyrimidine-6-car- pyrimidine-6-carboxylate (7f): Pale orange yellow
2.7c 7-Methyl-3-oxo-5-phenyl-2-piperidin-1-ylmethy-
◦
−1
boxylic acid ethyl ester (7c): Pale orange red solid, solid, yield 73%, M.p.: 254–255 C. IR (KBr) v cm :
◦
−1
yield 76%, M.p.:242–243 C. IR (KBr) v cm : 2974 3048, 2977 (CH), 1703 (C=O), 1618 (C=C), 1506
1
(
(
CH), 1701 (C=O), 1605 (C=C), 1495 (C=N), 1188 (C=N), 1197 (C-O). H NMR (400 MH
Z
, CDCl
), 1.78 (m, 4H,
-H, pyrrolidine),
), 4.11 (q, J=7.2
), 6.02 (s, 1H, C5-H), 6.78–7.29 (m,
3
) δ
1
C-O). H NMR (400 MH , CDCl ) δ ppm: 1.28 (t, ppm: 1.24 (t, J=7.2 Hz, 3H, CH
CH
3
Z
3
2
2
J=7.2 Hz, 3H, CH CH ), 1.64 (m,6H, C , C , C -H,
C
3
, C
4
-H, pyrrolidine), 2.64 (m, C
, C
5
2
3
3
4
5
piperidine), 2.51 (s, 3H, CH ), 3.42(m,4H, C , C -H, 2.34 (s, 3H, CH
), 3.79 (s, 3H, OCH
3
2
6
3
3
piperidine), 4.09 (q, J=7.2 Hz, 2H, CH CH ), 6.11 Hz, 2H, CH
CH
2
3
2
3
13
(
s, 1H, C5-H), 6.93–7.25 (m, 5H, Ar-H), 7.52 (s, 1H, 4H, Ar-H), 7.53 (s, 1H, =CH-N(CH ). C NMR
CH-N(CH ) ). C NMR (400 MH , CDCl ) δ ppm: (400 MH , CDCl ) δ ppm: 14.03, 22.99, 25.51, 55.53,
Z 3
4.16, 23.02, 24.42, 26.31, 54.49, 59.84, 60.30, 100.19, 57.52, 59.71, 61.23, 100.96, 118.01, 129.36–135.49,
18.03, 123.79–134.27, 140.44, 144.01, 155.57, 141.02, 144.19, 155.37, 161.29, 163.71, 166.32,
60.69, 164.72, 166.32, 167.11. %CHNS found (calc): 167.18. %CHNS found (calc): C 61.81 (61.67), H 5.89
2
)
2
13
=
2
2
Z
3
1
1
1
C 64.21 (64.23), H 6.12 (6.31), N 10.21 (10.37), S 7.79 (5.71), N 9.83 (9.92), S 7.50 (7.41).
7.61).
(
2.8 Procedure for the synthesis of tricyclic
2.7d 5-(3-Methoxy-phenyl)-7-methyl-3-oxo-2-piperi-
thiazolopyrimidine
din-1-ylmethylene-2,3-dihydro-5H-thia-zolo[3,2-a]py-
2
.8a Procedure for the synthesis of ethyl 3-amino-2-
rimidine-6-carboxylic acid ethyl ester (7d): Pale
◦
cyano-5-(3-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-
a]pyrimidine-6-carboxylate (9): To a warm solution
of KOH (10 mmol) and pyrimidine derivative (8)
orange red solid, yield 73%, M.p.:237–238 C. IR
−
1
(
(
KBr) v cm : 2945 (CH), 1700 (C=O), 1611
1
C=C), 1493 (C=N), 1196 (C-O). H NMR (400
(10 mmol) in ethanol (30 mL), bromomalononitrile
MH , CDCl ) δ ppm: 1.19 (t, J=7.2 Hz, 3H,
Z
3
(11 mmol) was added dropwise with constant stirring.
CH CH ), 1.66 (m,6H, C , C , C -H, piperidine), 2.49
2
3
3
4
5
The reaction mixture was stirred for 2 h. The solution
was allowed to stand at room temperature for some
time and the solid product precipitated. The precipitate
was filtered and recrystallized from ethanol.
(
(
(
(
s, 3H, CH ), 3.41(m,4H, C , C -H, piperidine), 3.76
3 2 6
s, 3H, OCH ), 4.10 (q, J=7.2 Hz, 2H, CH CH ), 6.16
3
2
3
s, 1H, C5-H), 6.76–7.26 (m, 4H, Ar-H), 7.56
13
s, 1H, =CH-N(CH ) ). C NMR (400 MH , CDCl )
2
2
Z
3
◦
Yellow solid, yield 88%, M.p.:238–239 C. IR (KBr)
δ ppm: 14.10, 22.96, 24.12, 26.54, 55.55, 57.42, 59.91,
−
1
v cm : 3373, 3329 (NH ) 2931 (CH), 2189 (C≡N)
6
1
4
6
1.10, 101.12, 117.53, 127.12–136.19, 141.19, 144.23,
2
1
703 (C=O), 1655 (C=C), 1566 (C=N), 1195 (C-O).
Z 3
55.54, 161.03, 163.91, 166.60, 167.33. Mass (m/z):
1
+
H NMR (400 MH , CDCl ) δ ppm: 1.25 (t, J = 7.1 Hz,
41.8 [M] . %CHNS found (calc): C 62.56 (62.39), H
3
4
6
H, CH CH ), 2.35 (s, 3H, CH ), 3.78(s, 3H, OCH ),
.16 (5.97), N 9.52 (9.38), S 7.26 (7.19).
2 3 3 3
.12 (q, J = 7.0 Hz, 2H, CH CH ), 4.75 (s, 2H, NH ),
2
3
2
13
.06 (s, 1H, C5-H), 6.84–6.94 (m, 4H, Ar-H). C NMR
2
.7e Ethyl 3,5-dihydro-7-methyl-3-oxo-5-phenyl-2-
(
400 MH , CDCl ) δ ppm:14.09, 23.06, 54.87, 60.06,
Z 3
((pyrrolidin-1-yl)methylene)-2H-thiazolo [3,2-a]pyri-
90.43, 102.32, 113.76, 118.42, 129.63, 132.63, 143.19,
midine-6-carboxylate (7e): Pale orange yellow solid,
yield 75%, M.p.:262–263 C. IR (KBr) v cm : IR
◦
−1
155.35, 157.99, 163.16, 164.09, 165.23. %CHNS found
(calc): C 58.36 (58.62), H 4.90 (5.06), N 15.12 (15.13),
S 8.66 (8.59).
−1
(
(
KBr νmax, cm ): 3052, 2976 (CH), 1707 (C=O), 1620
1
C=C), 1502 (C=N), 1190 (C-O). H NMR (400 MH ,
Z
CDCl ) δ ppm: 1.22 (t, J=7.2 Hz, 3H, CH CH ),
3
2
3
1
2
.78(m, 4H, C , C -H, pyrrolidine), 2.36 (s, 3H, CH ), 2.8b Procedure for the synthesis 2-cyano-3-(1-ethoxy-
3 4 3
.65 (m, C , C -H, pyrrolidine), 4.09 (q, J=7.2 Hz, 2H, ethylideneamino)-5-(3-methoxy-phenyl)-7-methyl-5H-
2
5
CH CH ), 6.07 (s, 1H, C5-H), 7.19–7.32 (m, 5H, Ar- thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester
2
3
13
H), 7.52 (s, 1H, =CH-N(CH ) ). C NMR (400 MH , (10): A mixture of 9 (1.85 g, 5 mmol) and triethy-
2
2
Z
CDCl ) δ ppm: 14.03, 23.10, 25.31, 54.43, 59.86, lorthoacetate (2 mL) was heated under reflux in acetic
3
61.01, 100.17, 118.33, 123.19–135.42, 139.94, 144.21, anhydride for 6 h, excess triethylorthoacetate and acetic

472
H Nagarajaiah et al.
anhydride was removed. The residue was treated with 1.43(s, 3H, CH ), 2.00 (s, 3H, CH ), 2.36 (s, 3H,
3
3
petroleum ether. The solid thus separated was filtered, CH ), 3.73(s, 3H, OCH ), 4.08 (q, J = 7.0 Hz, 2H,
3
3
washed and recrystallized with petroleum ether to CH CH ), 4.28 (q, J = 7.0 Hz, 2H, CH ), 5.94 (s, 1H,
2
3
2
13
afford light greenish yellow crystals.
C5-H), 6.76–7.23 (m, 4H, Ar-H). C NMR (400 MH ,
Z
◦
Yellow green solid, yield 83%, M.p.:110–111 C. CDCl ) δ ppm:14.11, 23.14, 25.08, 54.08, 54.89, 59.46,
3
−1
IR (KBr) v cm : 2977, 2935 (CH), 2224 (C≡N), 90.48, 102.30, 112.89, 113.05, 118.68, 129.63, 143.17,
703 (C=O), 1616 (C=C), 1541 (C=N), 1184 (C-O); 155.35, 158.97, 159.55, 163.23, 164.17, 165.46.
1
1
H NMR (400 MH , CDCl ) δ ppm: 1.21 (t, J = 7.1 %CHNS found (calc): C 58.96 (58.72), H 5.16 (5.33),
Z
3
Hz, 3H, CH CH3), 1.36 (t, J = 7.1 Hz, 3H, CH CH ), N 11.96 (12.01), S 6.84 (7.03).
2
2
3
R
O
CH COONH
O
3
4
R
EtOH warm
R O
N
2
S
R1
O
N
O
R1
2(a-d)
OHC
R O
N
2
HCl/EtOH Method-2
O
S
N
1
a, 1d, 1e
CH COONH
3
4
HN
R= H, OH
R = H, 4-COOH, 3-CN, 3-F
AcOH reflux
Method-1
S
O
1
R = Me/Et
2
3
Code
R
R1
R2
Code
2c
R
R1
R2
Et
2
2
a
H
H
Et
4-OH
4-OH
4-COOH
3-F
b
4-OH
3-CN
Me
2d
Me
Mechanism for hydrolysis
R
R
R
O
O
O
O
O
O
O
N
HCl
N
S
O
N
O
S
R1
O
R1
OH
S
O
N
R1
NH2
OH2
R
O
O
HN
O
S
R1
O
O
Scheme 1. Synthesis and hydrolysis of arylidene derivatives of thiazolopyrimidine.

Thiazolo[3,2-a]pyrimidines
473
2.8c Procedure for the synthesis 7-amino-8-imino- The H atoms were placed at calculated positions in the
4-(3-methoxy-phenyl)-2,6-dimethyl-7,8-dihydro-4H-9- riding model approximation, their temperature factors
thia-1,4a,5,7-tetraaza-fluorene-3-carboxylic acid ethyl were set to 1.2 times those of the equivalent isotropic
ester (11): A mixture of 10 (2.2 g, 5 mmol) and temperature factors of the parent atoms. All other
hydrazine hydrate (7 mL) was stirred at room tempera- non-H atoms were refined anisotropically. Molecu-
ture for 2 h and then diluted with ethanol (20 mL). The lar diagrams were generated using ORTEP.17 The
resulting fine solid suspension was filtered, washed mean plane calculation was done using the program
1
8
with ethanol and purified by recrystallization from
ethanol-dioxane mixture to afford analytically (TLC)
pure pale yellow granules.
PARST.
◦
Yellow solid, yield 62%, M.p.:225–226 C. IR (KBr)
2
.10 Anti-microbial activity
−1
v cm : 3361 (NH), 3232, 3190 (NH ), 2923 (CH),
2
1
697 (C=O), 1652 (C=C), 1492 (C=N), 1230 (C-O). Anti-microbial activities of the synthesized compounds
1
H NMR (400 MH , DMSO-d ) δ ppm: 1.15 (t, J=7.2 2d, 4a, 5a, 5b, 6a, 7a, 7d, 9 and 10 were screened
Z
6
Hz, 3H, CH CH ), 2.29 (s, 3H, CH ), 2.33 (s, 3H, against the two standard bacterial strains Staphylo-
2
3
3
CH ), 3.68 (s, 3H, OCH ), 4.06 (q, J=7.2 Hz, 2H, coccus aureus, E.coli and two standard fungal strains
3
3
CH CH ), 4.81 (s, 2H, NH2), 6.42 (s, 1H, C5-H of Aspergillus niger, Penicillium chrysogenum by Agar
2
3
thiazolopyrimidine), 6.78–7.21 (m, 4H, Ar-H), 8.97 diffusion method with 3 different concentrations (0.5,
1
3
19,20
(
s, 1H, = NH). C NMR (400 MH , DMSO-d ) δ ppm: 1.0, 2.0 mg/mL).
Z
6
1
1
1
4.11, 23.14, 25.08, 54.08, 54.89, 59.46, 90.48, 102.30,
For anti-bacterial activity test, media used was pep-
12.89, 113.05, 118.68, 129.63, 143.17, 155.35, tone 10 g, NaCl 10 g and yeast extract 5 g, agar 20 g
58.97, 159.55, 163.23, 164.17, 165.46. %CHNS found in 1000 mL distilled water. Initially, the stock cultures
(
calc): C 56.32 (56.42), H 5.20 (4.99), N 19.70 (19.83), of bacteria were revived by inoculating in broth media
◦
S 7.52 (7.59).
.9 X-ray diffraction analysis
Good quality single crystals of compounds 3, 5b and
and grown at 37 C for 18 h. The agar plates of the
above media were prepared and wells were made in the
plate. Each plate was inoculated with 18 h old cultures
2
−4
(100 μL, 10 CFU) and spread evenly on the plate.
After 20 min, the wells were filled with compound
at different concentrations. The control wells with
Gentamycin were also prepared. All the plates were
7
a were obtained by slow evaporation of ethanol.
The X-ray diffraction data, for the compounds 3,
b and 7a were collected on a Bruker Smart CCD
Area Detector System using MoKα (0.71073 Å) radi-
◦
5
incubated at 37 C for 24 h and the diameter of inhibition
zone were noted.
15
ation. The data were reduced using SAINT-Plus.
The structure was solved by Direct methods using
For anti-fungal activities media used was Czapek-
Dox Agar: Composition (g/L) Sucrose-30.0; Sodium
nitrate-2.0; K HPO -1.0, MgSO . 7H O-0.5; KCl-0.5;
16
SHELXS97 and refined by difference Fourier synthe-
2
4
4
2
16
ses using SHELXL97. The positions and anisotropic
displacement parameters of all non-hydrogen atoms
were included in the full-matrix least-square refine-
ment using SHELXL9716 and the refinement proce-
FeSO -0.01; Agar-20: Initially, the stock cultures
4
offungi were revived by inoculating in broth media and
◦
grown at 27 C for 48 h.
The agar plates of the above media were prepared
dures were carried out until convergence was reached. and wells were made in the plate. Each plate was
R
R
R
O
O
O
O
O
O
DMF-DMA
Mannich reaction
HCHO
O
N
O
N
O
N
S
S
N
morpholine
N
1
N
S
N
N
4
(a-d)
5(a-d)
a & 4b
O
R=H, 3-OMe, 4-OMe, 4-OH
Scheme 2. Synthesis of some new derivatives of thiazolopyrimidines.

474
H Nagarajaiah et al.
4
inoculated with 48 h old cultures (100 μL, 10 CFU) 3. Result and Discussion
and spread evenly on the plate. After 20 min, the wells
were filled with different concentrations of samples.
3.1 Chemistry
The control wells were filled with antibiotic. All the Compounds were synthesized by following procedure
◦
plates were incubated at 27 C for 72 h and the diam- depicted in the schemes 1, 2, 3 and 4. The starting
eter of inhibition zone were noted. The results of the materials 7-methyl-3-oxo-5-(substituted phenyl)-2,3-
anti-microbial activities are shown in table 3.
dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid
R
O
O
2-Amino benzoic acid
HOOC
NH
O
N
S
N
R
6a & 6b
O
6a; R=H, 6b; R=OMe
N
O
O
N
O
N
S
N
R
N
R =
1
5
a & 5b
O
O
5
a; R=H, 5b; R=OMe
O
N
N
20
Amines
S
R1
N
7(a-f)
R=H, OMe
Scheme 3. Synthesis of dimethyl amino-methylene derivatives of thiazolopyrimidines.
O
O
O
OEt
O
O
NH2
O
N
EtOH, KOH
CHBr(CN)2
CH C(OEt)3
CH3
EtO
NH
EtO
N
3
EtO
N
CN
CN
Ac O, Reflux
2
N
H
8
S
S
N
S
N
9
10
NH -NH , H O
2
2
2
O
CH3
O
N
NH2
N
EtO
N
NH
S
N
11
Scheme 4. Synthesis of tricyclic thiazolopyrimidine.

Thiazolo[3,2-a]pyrimidines
475
ethyl esters 1(a–e) were prepared by treating 6-methyl- 5 (a–d). In order to confirm the spectral data, one of
-(substituted phenyl)-2-thioxo-1,2,3,4-tetrahydro-py- the derivative 5b was subjected to single crystal X-ray
4
rimidine-5-carboxylic acid ethyl esters with chloro acetic diffraction technique. Crystal structure of compound 5b
acidin dioxane under reflux condition. These active showed that the product is Z-isomer. Treatment of com-
methylene compounds 1a, 1d and 1e were further pounds 5a and 5b with 2-amino benzoic acid gave the
allowed to react with substituted aromatic aldehydes corresponding secondary amine derivative. Reaction of
in presence of ammonium acetate to givearylidene compounds 5a and 5b with secondary amines likes
1
derivatives of thiazolopyrimidine. The H NMR spec- morpholine, piperidine or pyrrolidine taken in ethanol,
tra of compounds 2(a–d) indicate the absence of sig- on refluxing gave corresponding tertiaryamines 7 (a–f)
nals for the CH proton around δ 3.7–3.9 ppm and addi- (scheme 2). In addition to spectral technique, one of
2
tional signals in the aromatic region. Acid hydrolysis of the tertiary amine was subjected to single crystal X-ray
arylidene derivative 2a leads to the formation of diffraction technique. Crystal structure of compound 7a
thiazolid-2,4-one (3) via the rupture of endocyclic C=N showed the morpholine ring adopts chair conformation.
bond in pyrimidine ring by method 1. The hydrolyzed
Compound 8 was synthesized from well-known
component (3) was also obtained by an alternative Biginelli one pot cyclo-condensation reaction.21 The
method 2, which involves in situ condensation followed reaction of dihydropyrimidine (8) with bromomalonon-
by hydrolysis (scheme 1).
itrile in presence of strong base resulted in the forma-
Compounds 1a and 1b undergo Mannich reaction tion of compound 9. Product was confirmed by using
with different secondary amines yielding compounds spectral techniques. In the IR spectrum of compound
−1
4a and 4b. Further treatment of compounds 1(a–d) 9 there is an appearance of sharp peak at 2189 cm
with dimethylformamide–dimethylacetal (DMF-DMA) characteristic of nitrile group and two sharp peaks at
−
1
under reflux condition gave 2-dimethylaminomethylene- 3300–3150 cm correspond to -NH group and in the
2
1
7-methyl-3-oxo-5-(substituted phenyl)-2,3-dihydro-5H-
H NMR spectrum, appearance of signal at δ 4.75 ppm
thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl esters correspond to -NH confirming ring closure. Compound
2
Table 1. Crystal data and refinement parameters for compounds 3, 5b and 7a.
3
5b
7a
Formula
M
T /K
C10H7NO2S
205.23
C20H23N3O4S
401.47
C21H23N3O4S
413.48
296(2)
296(2)
296(2)
Crystal system
Space group
Monoclinic
P21/c
Monoclinic
P21/c
Monoclinic
P21/c
´
a/Å
9.4365(6)
15.4787(17)
9.6946(11)
12.3736(13)
12.2454(13)
´
b/Å
11.5294(8)
´
c/Å
8.1876(6)
95.5990(10)
13.0224(14)
90.836(2)
13.0093(13)
99.458(2)
o
β/( )
´
3
V /Å
886.54(11)
4, 1.538
1953.9(4)
4, 1.365
0.198
1944.4(3)
4, 1.413
0.201
Z, dcalcd/(g cm 3)
μ/mm
F(000)
−
−1
0.332
424
848
872
◦
θ range/( )
2.80 to 25.00
−11 <= h <= 11
1.32 to 27.00
−15 <= h <= 19
−12 <= k <= 12
−15 <= l <= 16
11280
1.67 to 27.00
−13 <= h <= 15
−14 <= k <= 15
−16 <= l <= 8
11413
Index ranges
−
13 <= k <= 13
−
9 <= l <= 7
Reflections collected
Independent
4506
1554
4209
4197
reflections
Completeness
[Rint = 0.0214]
[Rint = 0.0386]
[Rint = 0.0356]
99.4%
98.5 %
98.8%
Data/restraints/parameters
Goodness-of-fit onF2
R1, wR2 [I > 2σ(I)]
R1, wR2 (all data)
Largest diff. peak,
1554 /0/127
0.940
0.0347, 0.0998
0.0369, 0.1059
0.266, −0.363
4209/0/258
1.499
0.0671, 0.1763
0.0966, 0.2502
0.947, −0.774
4197/0/264
0.949
0.0619, 0.1644
0.0865, 0.2418
0.751, −0.761
−3
hole/(e A
)

476
H Nagarajaiah et al.
9
and triethylorthoacetate was refluxed in acetic anhy-
dride to give compound 10. IR spectrum shows the
−1
absence of peaks around 3300–3150 cm confir-
1
ming the absence of -NH group and from the H NMR
2
spectrum appearance of signals at δ 1.36, 1.45
and 4.28 ppm corresponds to additional -CH ,-CH
3
3
and -CH groups respectively. Further treatment of
2
compound 10 with hydrazine hydrate in ethanol
gave tricyclic thiazolopyrimidine 11. The ring system
obtained was confirmed by IR spectrum. The absence
−1
of peak at 2189 cm indicates that there is nonitrile
group, the appearance of peak at 3361 and peaks at
−1
3
232 and 3190 cm corresponds to -NH and -NH2
group.
(
a)
3.2 Crystallography
The details of crystal data and refinements are given
in table 1 for the compounds 3, 5b and 7a. Tables
2
a and 2b give respective hydrogen bond interactions.
The ORTEP view of the molecule with atomic labeling
thermal ellipsoids drawn at 50% probability) of 3, 5b
(
and 7a are shown in figures 1, 2a and 2b respectively.
Figures 3a, 3b and 3c show the packing of molecules in
the crystal structure.
Compounds 5b and 7a crystallize in the monoclinic
space group containing one molecule each in the asym-
metric unit. Both the compounds have almost simi-
(
b)
Figure 2. (a) ORTEP view of compound 5b, showing 50%
lar substituents at C2, C3, C5, C6 and C7. In com- probability ellipsoids and the atom numbering scheme. (b)
ORTEP view of compound 7a, showing 50% probability
ellipsoids and the atom numbering scheme.
pounds 5b and 7a, the aryl ring at C5 is positioned
22
axially to the pyrimidine ring with a dihedral angle
◦
of 89.88(8) and 89.66(8) respectively. Aryl ring in
both the compounds is projecting away from the plane it slightly deviates from the mean plane of thiazolopy-
◦
of the thiazolopyrimidine ring. The ethyl carboxylate rimidine with dihedral angle of 17.77(8) this may be
group at C6 in compound 7a is planar with respect to attributed to the presence of bulky group at C5. The
the thiazolopyrimidine ring whereas in compound 5b centralpyrimidine ring in compounds 5b and 7a adopt
22
twist boat conformation due to the deviation of C5
and N2 atom from the mean plane C6/C7/C9/N1 consti-
´
tuting ring by -0.295/-0.297(3)and -0.052/-0.066(3) Å
respectively. The two values separated by ‘/’ correspond
to two different compounds i.e. 5b and 7a. In com-
pound 5b, dimethylaminomethylene group adopts Z
configuration. The substituted morpholine ring at C17
of compound 7a adopts chair conformation with the
atoms N3 and O4 displaced from the mean plane of the
remaining ring atoms (C18/C19/C20/C21) by 0.6863
´
(
2) and −0.5735 (2) Å, respectively.
The crystal structure of the compound 5b is sta-
bilized by C-H. . .O and C-H. . .N interactions. There
are two types of C-H. . .O interactions, the former C8-
H8A. . .O4 interaction running along crystallographic
Figure 1. ORTEP diagram for the hydrolyzed compound 3.
‘b’ axis, whereas the later C12-H12. . .O1 interaction

Thiazolo[3,2-a]pyrimidines
477
running along crystallographic ‘c’ axis. Both resulted the case of compound 5b there are two types of C-
in two dimensional networks. The C-H. . .N interaction H. . .O interactions. Here one of the C-H. . .O interac-
generates bifurcated bonds from two donors, C17 and tion generates bifurcated bonds from two donors, C4
C18, to the same acceptor N2 along ‘c’ axis. The crystal and C14, to the same acceptor O4 along ‘a’ axis. The
structure is further stabilized by C4-H4B. . .Cg1 (Cg1 other two interactions C-H. . .O and C-H. . .N are resul-
is the centroid of aryl ring C11–C16) interaction with a ting in a helical pattern running along the ‘b’ axis
´
(
figure 3c). The crystal structure is also stabilized
distance of 2.842 Å (table 2a).
by C19-H19B. . .Cg2 (Cg2 is the centroid of aryl
The crystal structure of the compound 7a is also sta-
bilized by C-H. . .O and C-H. . .N interactions. As in ring C11–C16) interaction with a distance of 2.940 Å
´
Figure 3. (a) Packing of the compound 5b showing intermolecular C-H. . .O and C-H. . .N interactions. (b) Packing
of the compound 7a showing intermolecular bifurcated C-H. . .O interactions. (c) Packing of the compound 7a showing
intermolecular C-H. . .O and C-H. . .N interactions.
◦
Table 2a. C-H. . . π interaction and possible hydrogen bond distances and angles (Å, ) for compound 5b (D-donor; A-
acceptor; H-hydrogen).
D—H· · · A
D—H
H· · · A
D· · · A
D—H· · · A
C8-H8A. . .O4i
C12-H12. . .O1
C18-H18A. . .N2
0.970
0.930
0.970
0.930
0.960
2.428
2.537
2.725
2.554
2.842
3.302(4)
3.288(4)
3.639(5)
3.470(4)
3.733(4)
150
138
159
168
155
ii
iii
iv
C17-H17. . .N2
v
C4-H4B. . .Cg1
Symmetry code: (i) x, +y − 1, +z (ii) x, −y + 1/2, +z + 1/2 (iii) x, −y + 1/2, +z − 1/2 (iv) x, −y + 1/2, +z − 1/2 (v)
x, 1/2 − y, z − 1/2
◦
Table 2b. C-H. . . π interaction and possible hydrogen bond distances and angles (Å, ) for compound 7a (D-donor; A-
acceptor; H-hydrogen).
D—H· · ·A
D—H
H· · · A
D· · · A
D—H· · · A
C21–H21A...O1i
0.970
0.930
0.970
0.960
0.969
2.670
2.566
2.684
2.577
2.940
3.499(4)
3.477(4)
3.653(4)
3.534(4)
3.715(4)
144
166
177
174
137
ii
C14 -H14A...O4
iii
C18-H18B...N2
C4-H4A...O4
iii
iv
C19-H19B. . .Cg2
Symmetry code: (i) −x + 1, +y − 1/2, −z + 1/2 (ii) x + 1, +y, +z (iii) −x + 1, +y + 1/2, −z + 1/2 (iv) 1 − x, 1 − y, 1 − z

478
H Nagarajaiah et al.
Table 3. Inhibition zone diameter (mm) of synthesized compounds against testedbacterial strains by Agar diffusion method.
Bacteria Fungi
Compounds
E.coli
S. aureus
A. niger
P. crysogenium
Sample concentration 0.5 mg 1 mg 2 mg 0.5 mg 1 mg 2 mg 0.5 mg 1 mg 2 mg 0.5 mg 1 mg 2 mg
2
4
5
5
6
7
7
9
1
d
a
a
b
a
a
d
-
7
-
-
0
-
-
-
-
-
10
-
-
3
-
-
-
-
-
17
-
-
5
-
-
-
-
-
4
-
-
0
-
-
-
0
-
5
-
-
2
-
-
-
2
-
7
-
-
3
-
-
-
5
-
-
-
-
-
0
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0
2
00 μg 400 μg 800 μg 200 μg 400 μg 800 μg 200 μg 400 μg 800 μg 200 μg 400 μg 800 μg
Gentamicin
Amphotericin
2.6
ND
2.8
ND
3.1
ND
2.5
ND
2.7
ND
3.4
ND
ND
3
ND
5
ND
7
ND
0
ND
3
ND
5
Note: “-” Not Active, “ND” – Not Determined.
(table 2b). Finally, supramolecular assembly is further addition, crystal structures of two of the derivatives that
consolidated by π−π stacking interactions between yielded good quality crystals were verified by single
the thiazolopyrimidine rings. This interaction is not crystal X-ray diffraction. Crystal structures reveal that
observed in the case of compound 5b.
compounds 5b and 7a are Z-isomers. Crystal struc-
ture of compound 7a showed the substituted morpho-
line ring adopts chair conformation. In both the deriva-
tives, the ester at C6 adopts cis configuration with
respect to C6-C7 double bond, which is a prerequi-
site for the molecule to exhibit calcium channel mod-
ulatory activity. On screening all the compounds,
only compounds 4a, 6a, 7a, 9 and 10 exhibited good
anti-microbial activities at very low concentration of
3.3 Anti-microbial evaluation
The anti-microbial screening was done using agar dif-
fusion method using different strains of bacteria and
fungi. The results with the test compounds 2d, 4a, 5a,
23
5b, 6a, 7a, 7d, 9 and 10 reveal that only few compounds
exhibit antimicrobial activity. Gentamicin and Ampho-
tericin were used as reference to evaluate the potency of
tested compounds. Compounds 6a, 7a and 10 showed
moderate anti-microbial activity, while compound 4a
showed very good activity even at low concentration.
Compounds 2d, 5a, 5b, 7d and 9 did not show any
activity against the tested microorganisms. The result of
anti-microbial activity is tabulated in table 3.
0.5–2.0 mg/mL against Aspergillus niger, Penicillium
chrysogenum, Staphylococcus aureus and Escherichia
coli. using Gentamicin and Amphotericin as standards.
Supplementary Information
The CIF files are deposited at the Cambridge Crystal-
lographic Data Centre. The deposition number of com-
pounds 3, 5b and 7a are CCDC-966410, CCDC-975896
and CCDC-975899, respectively.
4
. Conclusion
This work reports the synthesis of a new series of thia-
zolopyrimidines. We have developed a new and conve-
nient synthetic method for the preparation of arylidene
derivatives of thiazolopyrimidine. During our studies
with thiazolopyrimidines, we have also noticed that
hydrolysis of arylidene derivative of thiazolopyrimi-
dine via rupture of endocyclic C=N bonds in pyrimi-
dine ring under acidic condition gives the same prod-
uct as that obtained by in situ condensation followed
by hydrolysis (scheme 1, method 1), for which a
mechanism has been proposed. The structures of the
products were confirmed by spectral techniques. In
Acknowledgements
NSB and HN thank the University Grants Commission,
New Delhi, India for the financial assistance.
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